Researchers find region of gene for inherited pancreatic cancer

Advance by Fred Hutchinson, UW and Pitt collaborators made possible with the help of "Family X" and a pioneering pancreatic-cancer screening program that saves lives

SEATTLE — Feb. 28, 2002 — Researchers at Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, in collaboration with investigators at the University of Pittsburgh School of Medicine, have mapped the location of a gene associated with inherited pancreatic cancer.

Study directors Leonid Kruglyak, Ph.D., a Fred Hutchinson statistical geneticist; Teresa Brentnall, M.D., a UW gastroenterologist; and David C. Whitcomb, M.D., Ph.D., head of gastroenterology at Pitt; and colleagues report their findings in the early electronic edition of the April issue of the American Journal of Human Genetics.

Other members of the research team include Michael Eberle, Ph.D., of Fred Hutchinson and Roland Pfutzer, Ph.D., of Pitt, who shared first authorship of the paper.

"This is the first genetic defect that's been linked directly to pancreatic cancer," said Kruglyak, whose Fred Hutchinson team performed the genetic-data crunching that mapped the gene to the long arm of chromosome 4. Having found the gene's neighborhood, in a fairly large region called 4q32-34, the researchers now aim to close in on its specific address.

"There are about 100 genes in the region, a fair amount of data to sift through. I would think we'd probably have the gene sequenced within a year, but ultimately it's truly a matter of luck," said Brentnall, UW associate professor of medicine and pathology.

Finding the gene promises to shed new light on how pancreatic cancer develops, ultimately opening new avenues for preventing, detecting and treating this particularly deadly malignancy, which has, until now, largely remained an enigma in cancer research.

"You can't touch it or feel it. You can't find it on physical exam. The cancer is asymptomatic, strikes later in life and is rapidly lethal — most people die within six months of diagnosis," Brentnall said. "Such factors have impeded the collection of material for study and have hampered our ability to understand the natural history of the disease, resulting in very little headway in the past hundred years.

"This finding will open up an area that was previously a black box," she said.

Gathering enough genetic data to help pry open that box was made possible, first and foremost, by the cooperation of a large Northwestern clan widely known in scientific circles as "Family X," the largest pancreatic-cancer family ever studied. (The family chooses to remain anonymous.)

"What makes this family so remarkable is that it is extremely large and has a very high incidence of early onset pancreatic cancer. Most family members have been diagnosed in their mid-40s and the age of diagnosis just keeps getting younger with every generation," said Brentnall, who has been working with Family X, scientifically and clinically, for more than seven years.

Of the 20 affected family members studied (18 with pancreatic cancer or evidence of precancerous changes, called dysplasia, and two with a condition called pancreatic insufficiency), nine have died of the disease, including five out of six brothers.

"Not a good family to be a member of in this regard," said Kruglyak, who also has lost a family member to the disease, a cousin to whom he dedicates his work on the project.

But Family X is an excellent family for studying inherited pancreatic cancer, which accounts for about 10 percent of such malignancies.

"Other pancreatic-cancer families that have been studied have been too small to be informative, as they tend to have just one or two affected individuals," said Kruglyak, an associate member of Fred Hutchinson's Human Biology and Public Health Sciences divisions and a Howard Hughes Medical Institute investigator.

Another crucial aid to data collection was the development of a pioneering pancreatic-cancer screening program for high-risk individuals, based at UW, that uses endoscopic imaging techniques to help detect precancerous changes in the pancreas while there's still time to intervene surgically — before cancer develops.

All members of Family X who've had abnormalities detected endoscopically — and precancerous changes confirmed through tissue biopsy — have opted for preventive removal of the pancreas, an organ that contains insulin-producing cells key to blood-sugar regulation. The organ also produces enzymes that aid digestion.

Those who undergo pancreatotomy must take insulin and digestive enzymes for the rest of their lives to compensate for the organ's removal. Although all of these patients become insulin-dependent diabetics, they can enjoy long, productive lives, said Brentnall, founder and director of UW's pancreatic-cancer surveillance program, the first of its kind in the nation. The program currently serves 35 patients from more than a dozen families. Similar screening programs are now in place at several other institutions, including Johns Hopkins and the Mayo Clinic.

The DNA samples from Family X collected by Brentnall's group were genotyped by a team of Pitt researchers led by Whitcomb, professor of medicine, cell biology and physiology, and human genetics, and director of the university's Center for Genomic Sciences.

In genotyping, Whitcomb and colleagues sequenced DNA from hundreds of areas of the genome known to contain a high degree of genetic variability. This information then served as a reference point for Kruglyak's team at Fred Hutchinson, who provided linkage analysis, using sophisticated computer software to determine which genetic variations are always present in family members with pancreatic cancer or its precursor, dysplasia.

Virutally every member of Family X with pancreatic cancer or dysplasia was found to harbor a specific genetic marker on the long arm of chromosome 4, where the single-gene mutation responsible for pancreatic cancer is thought to lurk. Equally important, none of the unaffected family members inherited this marker, a testament to its clinical and statistical significance.

Finding this marker would not have been possible without the collaboration among the Fred Hutchinson, UW and Pitt researchers, Whitcomb said. "Those of use who work with complex and mysterious medical problems like pancreatic cancer recognize that no independent physician or scientist can go from the bed to the bench and back again alone. It takes physician-scientist teamwork, as demonstrated here, to make the big breakthroughs."

While this scientific break ultimately may lead to the discovery of a specific pancreatic-cancer gene, already it shows promise for screening the disease in future generations of Family X.

"Just having these markers, in principle, has diagnostic implications for this specific family," Kruglyak said. "With a simple blood test, we should at least now be able to tell, with good confidence, whether new members of this family are likely to have inherited the gene.

"Once the actual gene is found, if it turns out to be commonly mutated in all forms of pancreatic cancer — not just the inherited type — it could be used as a marker for broad screening. Knowing and understanding the gene's pathways to cancer also could lead to new therapeutic developments," said Kruglyak, also an affiliate professor of genome sciences at the UW School of Medicine.

Of the 29,000 Americans who this year will learn they have pancreatic cancer, 28,900 will die within 12 months of diagnosis. While pancreatic cancer is the fifth leading cause of cancer death in the United States, it is one of the least well-funded areas of cancer research.

Support for this study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Mental Health; the National Pancreas Foundation; the Lustgarten Foundation; the Center for Genomic Sciences, University of Pittsburgh; and the Chiron Corporation.

Editor's Note
To obtain a copy of the paper, "A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34," go to the American Journal of Human Genetics Web site, www.ajhg.org/journal/.

Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical and research partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 38 nationwide. For more information, visit the center's Web site at www.fhcrc.org.

University of Washington
The University of Washington's faculty includes five Nobel Prize winners, five MacArthur Fellows and 40 members of the prestigious National Academy of Sciences. Since 1975, the UW has been the nation's top public university in receipt of federal research funds, and since 1992 it has been second among all U.S. universities, public and private. For more information, visit the University's Web site at www.washington.edu.

University of Pittsburgh School of Medicine
The University of Pittsburgh School of Medicine is consistently ranked among the nation's leading medical schools. It is one of the university's six Schools of the Health Sciences, which include the schools of Nursing, Dental Medicine, Pharmacy, Health and Rehabilitation Sciences and the Graduate School of Public Health. The many areas for which its faculty and programs are internationally recognized include oncology, psychiatry, genetics, transplantation and public health. For more information visit the Division of Gastroenteroloy, Hepatology and Nutrition's Web site at www.medschool.pitt.edu.